This application claims the benefit of Great Britain Application No. 9927874.9, filed Nov. 25, 1999; Great Britain Application No. 0018651.0, filed Jul. 28, 2000; and Great Britain Application No. 0009602.4, filed Apr. 18, 2000.
The present invention relates to a class of substituted pyrazolotriazine derivatives and to their use in therapy. More particularly, this invention is concerned with substituted pyrazolo[1,5-d][1,2,4]triazine derivatives which are ligands for GABAA receptors containing the xcex15 subunit and are therefore useful in therapy where cognition enhancement is required.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to thirteen (six xcex1 subunits, three xcex2 subunits, three xcex3 subunits and one xcex4 subunit). It may be that further subunits remain to be discovered; however, none has been reported since 1993.
Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an xcex1 subunit, a xcex2 subunit and a xcex3 subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, a xcex4 subunit also exists, but is apparently uncommon in the native receptor.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one xcex1, one xcex2 and one xcex4 subunit from a repertoire of thirteen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include xcex11xcex22xcex32, xcex12xcex22/3xcex32, xcex13xcex2xcex32/3, xcex12xcex2xcex31, xcex15xcex23xcex32/3, xcex16xcex2xcex32, xcex16xcex2xcex4 and xcex14xcex2xcex4. Subtype assemblies containing an xcex11 subunit are present in most areas of the brain and account for over 40% of GABAA receptors in the rat. Subtype assemblies containing xcex12 and xcex13 subunits respectively account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an xcex15 subunit are primarily hippocampal and represent about 4% of receptors in the rat.
A characteristic property of some GABAA receptors is the presence of a number of modulatory sites, of which the most explored is the benzodiazepine (BZ) binding site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the xcex11 subunit in combination with xcex22 and xcex32. This is the most abundant GABAA receptor subtype, representing almost half of all GABAA receptors in the brain.
A number of dementing illnesses such as Alzheimer""s disease are characterised by a progressive deterioration in cognition in the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatment, for example for subjects suffering from a dementing illness.
It has been reported by McNamara and Skelton in Psychobiology, 21:101-108, that the benzodiazepine receptor inverse agonist xcex2-CCM enhanced spatial learning in the Morris watermaze. However, xcex2-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant which makes it clear that they cannot be used as cognition enhancing agents in humans.
However, we have now discovered that it is possible to obtain medicaments which have cognition enhancing effects which may be employed with less risk of proconvulsant effects previously described with benzodiazepine receptor partial or full inverse agonists.
The present invention is directed to compounds according to Formula (I) or a pharmaceutically acceptable salt thereof that are GABA-A Alpha 5 ligands useful for enhancing cognition: 
It has now been discovered that use of an xcex15 receptor partial or full inverse agonist which is relatively free of activity at xcex11 and/or xcex12 and/or xcex13 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition but in which proconvulsant activity is reduced or eliminated. Inverse agonists at xcex15 which are not free of activity at xcex11 and/or xcex12 and/or xcex13 but which are functionally selective for xcex15 can also be used. Inverse agonists which are both selective for xcex15 and are relatively free of activity at xcex11, xcex12 and xcex13 receptor binding sites are preferred.
The present invention provides a compound of formula I, or a salt thereof: 
wherein
R1 represents halogen; or C1-6alkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-8 bicycloalkyl, C6-10aryl, C3-7 heterocycloalkyl, heteroaryl defined as an aromatic ring containing either 6 atoms, 1, 2, or 3 of which are nitrogen, or 5 atoms, 1, 2 or 3 of which are independently chosen from oxygen, nitrogen or sulphur but not more than one of which is oxygen or sulphur, or di(C1-6)alkylamino, any of which groups may be optionally substituted with one or more substituents selected from halogen, R3, OR3, OC(O)R3, NR4R5, NR4R5(C1-6)alkyl, NR4R5C(O), NR4R5C(O)(C1-6)alkyl, CN, cyano(C1-6)alkyl or R6;
R3 represents C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkyl(C1-6)alkyl, cyano(C1-6)alkyl, hydroxyC1-6alkyl and R3 is optionally mono, di or trifluorinated;
R4 and R5 are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or CF3 or R4 and R5, together with a nitrogen atom to which they are commonly attached, form a 4-7 membered heteroaliphatic ring containing the said nitrogen atom and optionally one other heteroatom selected from O, N and S, which ring is optionally substituted by one or more R3 groups;
R6 is C6-10aryl, C6-10aryl (C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, where heteroaryl is defined as above, and R6 is optionally substituted by one, two or three substituents independently chosen from halogen atoms and C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C2-4alkenyloxy and C2-4alkynyloxy groups each of which groups is unsubstituted or substituted by one, two or three halogen atoms;
L is O, S or NRn where Rn is H, C1-6alkyl or C3-6cycloalkyl;
W is: C1-6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted by one or more groups chosen from halogen, amino, nitro, cyano, hydroxy and halogen; hydrogen; halogen; amino; nitro; cyano; hydroxy; or halogen;
X is NR4R5; or X is a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur, or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, the 5- or 6-membered heteroaromatic ring being optionally fused to a benzene or pyridine ring and the heteroaromatic ring being optionally substituted by Rx and/or Ry and/or Rz, where Rx is halogen, R3, OR3, OC(O)R3, C(O)OR3, NR4R5, NR4C(O)R5, OH, tri(C1-6alkyl)silylC1-6alkoxyC1-4alkyl, CN or R6, Ry is halogen, R3, OR3, OC(O)R3, NR4R5, NR4C(O)R5, NR4R5(C1-6)alkyl or CN and Rz is R3, OR3 or OC(O)R3, providing that when X is a pyridine derivative, the pyridine ring is optionally in the form of the N-oxide, and providing that when X is a tetrazole derivative it is protected by a C1-4alkyl group; or X is phenyl optionally substituted by one, two or three groups independently selected from halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl;
Y is optionally branched C1-4alkylene optionally substituted by an oxo group or Y is a group (CH2)jO wherein the oxygen atom is nearest the group X and j is 2, 3 or 4; and
Z represents a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur and providing that when one of the atoms is oxygen or sulphur then at least one nitrogen atom is also present, or a 6-membered heteroaromatic ring containing 2 or 3 nitrogen atoms with the exception of pyrazine, any of which rings may be optionally substituted with one or more substituents selected from halogen, R3, OR3, OC(O)R3, NR4R5, NR4R5(C1-6)alkyl, NR4R5C(O), NR4R5C(O)(C1-6)alkyl, CN, cyano(C1-6)alkyl or R6.
The invention also provides a compound according to Formula I above, or a pharmaceutically acceptable salt thereof, wherein R1, L, Y and Z are as defined above and X is a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur, or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, the 5- or 6-membered heteroaromatic ring being optionally fused to a benzene ring and the heteroaromatic ring being optionally substituted by Rx and/or Ry and/or Rz, where Rx is halogen, R3, OR3, OC(O)R3, NR4R5, NR4C(O)R5, tri(C1-6alkyl)silylC1-6alkoxyC1-4alkyl, CN or R6, Ry is halogen, R3, OR3, OC(O)R3, NR4R5, NR4C(O)R5, NR4R5(C1-6)alkyl or CN and Rz is R3, OR3 or OC(O)R3, providing that when X is a pyridine derivative, the pyridine ring is optionally in the form of the N-oxide, and providing that when X is a tetrazole derivative it is protected by a C1-4alkyl group; or X is phenyl optionally substituted by one, two or three groups independently selected from halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl.
As used herein, the expression xe2x80x9cC1-6alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as xe2x80x9cC1-4alkylxe2x80x9d, xe2x80x9cC2-4alkenylxe2x80x9d, xe2x80x9cC2-6alkenylxe2x80x9d, xe2x80x9chydroxyC1-6alkylxe2x80x9d, xe2x80x9cC2-4alkylxe2x80x9d and xe2x80x9cC2-6alkynylxe2x80x9d are to be construed in an analogous manner.
The expression xe2x80x9cC3-6cycloalkylxe2x80x9d as used herein includes cyclic propyl, butyl, pentyl and hexyl groups such as cyclopropyl and cyclohexyl.
The expression xe2x80x9cC3-6 cycloalkyl(C1-6)alkylxe2x80x9d as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
Typical C4-7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.
The expression xe2x80x9cC1-4alkylenexe2x80x9d as used herein refers to alkanediyl groups of up to 4 carbon atoms in which the unsatisfied valencies reside on the same carbon atom or on different carbon atoms.
Typical C6-8 bicycloalkyl groups include bicyclo[2.1.1]hexyl and bicyclo[2.2.1]heptyl.
Typical aryl groups include phenyl and naphthyl, preferably phenyl.
The expression xe2x80x9caryl(C1-6)alkylxe2x80x9d as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
Unless otherwise specified, 5- and 6-membered heteroaromatic rings shall include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused analogues thereof A suitable 5-membered heteroaromatic ring containing four nitrogen atoms is tetrazolyl. Suitable 6-membered heteroaromatic rings containing three nitrogen atoms include 1,2,4-triazine and 1,3,5-triazine. When a heteroaromatic ring comprises a hydroxy group as a substituent, and keto-enol tautomerism is possible, both tautomers are included within the scope of the invention. Thus, for example, a 3-hydroxy-1,2,4-triazole ring will be considered equivalent to the 3-keto tautomer.
The expression xe2x80x9cheteroaryl(C1-6)alkylxe2x80x9d as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
As used herein the term xe2x80x9cC1-6alkoxyxe2x80x9d includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy, butoxy, pentoxy and hexoxy groups, including cyclopropylmethoxy. Derived expressions such as xe2x80x9cC2-6alkenyloxyxe2x80x9d, xe2x80x9cC2-6alkynyloxyxe2x80x9d, xe2x80x9cC1-4alkoxyxe2x80x9d, xe2x80x9cC2-4alkenyloxyxe2x80x9d and xe2x80x9cC2-4alkyloxyxe2x80x9d should be construed in an analogous manner.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Suitably, the substituent R1 in the compounds of formula I above represents halogen; or C1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted. R1 may be unsubstituted. R1 may be mono substituted.
Suitable values for the substituent R1 include bromo, tert-butyl, 1,1-dimethylpropyl, phenyl, pyridinyl, furyl or thienyl, any of which groups may be optionally substituted by one or two substituents.
Examples of typical optional substituents on the group R1 include methyl, fluoro, chloro and trifluoromethyl. Particular substituents include fluoro, chloro and trifluoromethyl, especially fluoro.
Typical examples of suitable values for the group R1 include bromo, tert-butyl, 1,1-dimethylpropyl, phenyl, pyridinyl, furyl and thienyl.
Further examples of suitable values for the substituent R1 include methyl, ethyl, isopropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, bicyclo[2.1.1]hex-1-yl, bicyclo[2.2.1]hept-1-yl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, chloro-thienyl and diethylamino.
In preferred embodiments, the substituent R1 represents bromo, thienyl, tert-butyl, phenyl or furyl, especially bromo, tert-butyl, phenyl or furyl. Favourably, R1 represents tert-butyl. R1 may also be hydroxytertbutyl or ethenyl.
R3 is preferably C1-4alkyl, C2-4alkenyl, C2-4alkynyl or hydroxyC1-4alkyl and is optionally mono, di or trifluorinated. Most particularly R3 is C1-2alkyl, C2alkenyl or hydroxyC1-2alkyl optionally substituted with one, two or three halogen atoms.
R4 and R5 are preferably each independently hydrogen, C1-4alkyl, C2-4alkenyl or C2-4alkynyl or R4 and R5, together with the nitrogen atom to which they are attached, form a 4-6 membered heteroaliphatic ring containing the said nitrogen atom and optionally one other heteroatom chosen from oxygen and nitrogen.
R6 is preferably phenyl or pyridyl, optionally substituted by halogen, or C1-4alkyl. R6 is especially pyridyl.
Preferably L is an oxygen atom. L may also be S or NRn in which Rn is preferably hydrogen or methyl. Rn may be hydrogen.
W is generally C1-4alkyl optionally substituted by halogen or hydroxy; or W is hydrogen, halogen or hydroxy. W is particularly hydrogen or C1-6alkyl, especially methyl or hydrogen. Generally W is hydrogen.
X may be a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur, or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, the 5- or 6-membered heteroaromatic ring being optionally fused to a benzene or pyridine ring and the heteroaromatic ring being optionally substituted by Rx and/or Ry and/or Rz , where Rx is halogen, R3, OR3, OC(O)R3, NR4R5, NR4C(O)R5, OH, tri(C1-6alkyl)silylC1-6alkoxyC1-4alkyl, CN or R6, Ry is halogen, R3, OR3, OC(O)R3, NR4R5, NR4C(O)R5, NR4R5(C1-6)alkyl or CN and Rz is R3, OR3 or OC(O)R3, providing that when X is a pyridine derivative, the pyridine ring is optionally in the form of the N-oxide, and providing that when X is a tetrazole derivative it is protected by a C1-4alkyl group; or X is phenyl optionally substituted by one, two or three groups independently selected from halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl.
X is generally: pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl optionally substituted by a halogen atom or a group R3, OR3, NR4R5 or a five membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, and X is optionally fused to a benzene ring; a 5-membered heteroaromatic ring containing 2 or 3 heteroatoms chosen from oxygen, sulphur and nitrogen, at most one of the heteroatoms being oxygen or sulphur, which is unsubstituted or substituted by one, two or three groups independently chosen from halogen and R3, or which is substituted by a pyridyl, phenyl or benzyl ring which ring is optionally independently substituted by one, two or three halogen atoms or C1-6alkyl or CF3 groups; or phenyl optionally substituted by one, two or three independently chosen halogen atoms.
Alternatively, X may represent a 5-membered heteroaromatic ring containing 2 or 3 heteroatoms chosen from oxygen, sulphur and nitrogen, at most one of the heteroatoms being oxygen or sulphur, which is fused to a benzene or pyridine ring, or which is substituted by NH2 or by OH which may exist as the keto tautomer; or X may represent a tetrazole ring bearing a C1-4alkyl substituent.
When X is a substituted 6-membered heteroaromatic ring: Rx is preferably halogen, R3, OR3, NR4R5 or a five-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms and more preferably methyl, CF3, methoxy, bromine, chlorine, isopropoxy, dimethylamino or a five-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms; and Ry and Rz are preferably absent.
When X is a substituted 5-membered heteroaromatic ring: Rx is preferably halogen, R3 or a pyridyl, phenyl or benzyl ring, which ring is optionally independently substituted by one, two or three halogen atoms or C1-6alkyl or CF3 groups, and more preferably Rx is methyl, CF3, chlorine or a phenyl, pyridyl or benzyl ring which ring is unsubstituted or substituted by chlorine or CF3; and RY and Rz are preferably halogen or R3 or are absent, and more preferably are methyl, CF3 or chlorine, or are absent.
In one embodiment X is substituted by CH2NR4R5 or CH2CH2NR4R5.
Specific values of X are 2-pyridyl, 1-methyl-1,2,4-triazol-3-yl, 2-methyl-1,2, 4-triazol-3-yl, 1-methyl-1,2,3-triazol-4-yl, 5-methylisoxazol-3-yl, 1,2,4-oxadiazol-3-yl, and 2-methylthiazol-4-yl.
Further specific values of X are 1-methyl-1,2,3-triazol-5-yl, 5-oxo-1H, 4H-1,2,4-triazol-3-yl, 6-trifluoromethylpyrid-3-yl, 1-methylimidazol-2-yl, thiazol-4-yl, 2-aminothiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, pyridazin-3-yl, pyrazinyl, quinoxalin-2-yl, pyrimidin-4-yl, 1-methyltetrazol-5-yl, 5-(pyrid-4-yl)-2H-1,2,4-triazol-3-yl, oxazolo[4,5-b]pyridine-2-yl, 2-methylpyrazol-3-yl, 1-methylpyrazol-3-yl and pyrimidin-5-yl.
Yet further specific examples of X are 5-(piperidin-1-ylmethyl)pyridin-2-yl, 2-(2-(azetidin-1-yl)ethyl)pyridin-5-yl, 2-(2-(morpholin-4-yl)ethyl)pyridin-5-yl, 2-(2-(piperazin-1-yl)ethyl)pyridin-5-yl, 2-(2-(piperidin-1-yl)ethyl)pyridin-5-yl, 2-(2-(N,N-dimethylamino)ethyl)pyridin-5-yl, 2-(2-aminoethyl)pyridin-5-yl, 2-(2-aminoethyl)-1,2,4-triazol-3-yl, 2-(morpholin-4-ylmethyl)pyridin-5-yl, 2-hydroxymethylpyridin-5-yl, 5-(4-methylpiperazin-1-ylmethyl)pyridin-2-yl, 5-(azetidin-1-ylmethyl)pyridin-2-yl, 5-(morpholin-4-ylmethyl)pyridin-2-yl, 4-hydroxymethyl-1-methyl-1,2,3-triazol-5-yl, 5-aminomethylpyridin-2-yl, 5-(N,N-dimethylaminomethyl)pyridin-2-yl, 1-methyl-3-hydroxymethyl-1,2,4-triazol-5-yl, 1-methyl-3-(morpholin-4-ylmethyl)-1,2,4-triazol-5-yl, 1-methyl-3-(piperidin-1-ylmethyl)-1,2,4-triazol-5-yl, 6-hydroxymethylpyridin-2-yl, 6-(2-(morpholino-4-yl)ethyl)pyridin-2-yl, 6-(2-(piperazin-1-yl)ethyl)pyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 6-(2-(piperidin-1-yl)ethyl)pyridin-2-yl, 1-methyl-3-(azetidin-1-ylmethyl)-1,2,4-triazol-5-yl, 1-methyl-3-((2,6-cisdimethylpiperidin-1-yl)methyl)-1,2,4-triazol-5-yl, 2-methyl-3-hydroxymethyl-1,2,4-triazol-5-yl, 2-methyl-3-(N,N-dimethylaminomethyl)-1,2,4-triazol-5-yl, 2-methyl-3-(N,N-diethylaminomethyl)-1,2,4-triazol-5-yl, 1-methyl-3-(N,N-dimethylaminomethyl)-1,2,4-triazol-5-yl, 1-methyl-3-(N,N-diethylaminomethyl)-1,2,4-triazol-5-yl, 1-methyl-3-(2-(N,N-diethylamino)ethyl)-1,2,4-triazol-5-yl, 5-(N-ethylaminomethyl)pyridin-2-yl, 5-(N,N-diethylaminomethyl)pyridin-2-yl and dimethylamino.
Apt values for Y include CH2, CH(CH3), CH2CH2 and CH2CH2CH2 optionally substituted by an oxo group, and CH2CH2O and CH2CH2CH2O. For example, Y can be CH2, CH2CH2, CH2CH2CH2, CH2CH2O or CH2CH2CH2O. Preferably Y is CH2 or CH2CH2 and most preferably CH2. Y may be CH2C(O).
From the foregoing it will be understood that particularly suitable groups L-Y-X are OCH2X groups where X is pyridyl or triazolyl, particularly 1,2,4-triazol-3-yl substituted with methyl in the 1- or 2-position.
Suitable values for Z include optionally substituted pyrimidinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl groups.
Z is very aptly an optionally substituted 5-membered heteroaromatic ring containing one oxygen and one or two nitrogen ring atoms.
Favoured values for Z include optionally substituted isoxazoles and oxadiazoles.
Typical substituents on Z include C1-6alkyl, C3-6cycloalkyl, hydroxyC1-6alkyl, pyridyl, thienyl or amino, particularly methyl, ethyl, isopropyl, cyclopropyl, thienyl or pyridyl.
Z may be unsubstituted.
Z may very aptly be substituted by methyl.
Particular values of Z include 5-methylisoxazol-3-yl.
Further specific values of Z are 5-ethenylisoxazol-3-yl, 5-hydroxymethylisoxazol-3-yl, 5-(2-aminoethyl)isoxazol-3-yl, 5-aminomethylisoxazol-3-yl, 5-(2-(tertiarybutoxycarbonylamino)ethyl)isoxazol-3-yl, iodo, 5-(2-hydroxyethyl)isoxazol-3-yl, 5-(2-(azetidin-1-yl)ethyl)isoxazol-3-yl and 5-(2-(morpholin-4-yl)ethyl)isoxazol-3-yl.
A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and pharmaceutically acceptable salts thereof: 
wherein
R1a represents bromo, tert-butyl, 1,1-dimethylpropyl, phenyl, fluorophenyl, difluorophenyl, chlorophenyl, trifluoromethylphenyl, pyridinyl, furyl or thienyl;
Xxe2x80x2 represents phenyl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, thiadiazolyl, benzimidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, oxazolopyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl or quinoxalinyl, any of which groups may be optionally substituted by one or more of C1-6 alkyl, amino, pyridyl, CF3, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, cyano, cyano(C1-6)alkyl, hydroxymethyl, C1-6alkoxy, C3-6cycloalkyl(C1-6)alkoxy, hydroxy or the keto tautomer thereof, di(C1-6)alkylamino(C1-6)alkyl, amino(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl and morpholinyl(C1-6)alkyl; and
Zxe2x80x2 represents a 5-membered heteroaromatic ring containing one oxygen and one or two nitrogen ring atoms which is optionally substituted with C1-6alkyl or C1-6alkoxy.
In a subset of the compound of Formula IIA, Xxe2x80x2 represents phenyl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, oxazolopyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl or quinoxalinyl, any of which groups may be optionally substituted by one or more of C1-6 alkyl, CF3, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, cyano, cyano(C1-6)alkyl, hydroxymethyl, C1-6alkoxy, C3-6cycloalkyl(C1-6)alkoxy, hydroxy or the keto tautomer thereof, di(C1-6)alkylamino(C1-6)alkyl, amino(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl and morpholinyl(C1-6)alkyl.
Illustrative values of specific substituents on the group Xxe2x80x2 include methyl, ethyl, n-propyl, isopropyl, benzyl, pyridinylmethyl, chloro, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylmethyl.
Further illustrative values of specific substituents on the group Xxe2x80x2 include trifluoromethyl, amino, pyridyl and hydroxy or its keto tautomer.
Selected substituents for the group Xxe2x80x2 include methyl, ethyl, n-propyl, and isopropyl, especially methyl.
Further selected substituents for the group Xxe2x80x2 include trifluoromethyl, amino, pyridyl and hydroxy or its keto tautomer.
Specific values of Xxe2x80x2 include pyridyl, methyl-triazolyl, ethyl-triazolyl, propyl-triazolyl and isopropyl-triazolyl.
Further specific values of Xxe2x80x2 include 1,2,4-oxadiazolyl, methyl-thiazolyl, 5-hydroxy-1,2,4-triazolyl (which is equivalent to 5-oxo-1H, 4H-1,2,4-triazolyl), trifluoromethylpyridyl, methyl-imidazolyl, thiazolyl, amino-thiazolyl, amino-1,2,4-thiadiazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, pyrimidinyl, methyl-tetrazolyl, pyridyl-triazolyl, oxazolopyridinyl and methyl-pyrazolyl.
A favoured value of Xxe2x80x2 is methyl-triazolyl.
A particular subset of the compounds of formula IIA above is represented by the compounds of formula IIB, and pharmaceutically acceptable salts thereof: 
wherein
R1b represents bromo, thienyl, tert-butyl, phenyl or furyl; and
R7 represents hydrogen, methyl, ethyl, n-propyl or isopropyl.
In a subset of the compound of Formula IIB, R1b represents bromo, tert-butyl, phenyl or furyl.
In a particular embodiment of the compounds of formula IIB above, R7 represents methyl.
Particular compounds within the scope of the present invention include:
7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-3-phenylpyrazolo[1,5-d][1,2,4]triazine;
3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazolo [1,5-d][1,2, 4]triazine;
3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-[1,2,4]triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;
3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(pyrid-2-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;
3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(pyrid-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine; and
3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(pyrid-4-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;
and the pharmaceutically acceptable salts thereof.
The compounds of the present invention have a good binding affinity (Ki) for the xcex15 subunit of the GABAA receptor. In a preferred embodiment the compounds of the invention are binding selective for the xcex15 subunit relative to the xcex11, xcex12 and xcex13 subunits. In another preferred embodiment the compounds are functionally selective for the xcex15 subunit as partial or full inverse agonists whilst substantially being antagonists at the xcex11, xcex12 and xcex13 subunits.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The present invention also provides a compound of the invention for use in a method of treatment of the human body. Preferably the treatment is for a condition associated with GABAA receptors comprising the xcex15 subunit and/or for the enhancement of cognition. Preferably the condition is a neurological deficit with an associated cognitive disorder such as a dementing illness such as Alzheimer""s disease. Other conditions to be treated include cognition deficits due to traumatic injury, stroke, Parkinson""s disease, Downs syndrome, age related memory deficits, attention deficit disorder and the like.
The present invention further provides the use of a compound of the present invention in the manufacture of a medicament for the enhancement of cognition, preferably in a human suffering from a dementing illness such as Alzheimer""s disease.
Also disclosed is a method of treatment of a subject suffering from a cognition deficit, such as that resulting from a dementing illness such as Alzheimer""s disease, which comprises administering to that subject an effective amount of a compound according to the present invention.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
For the enhancement of cognition, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg of body weight per day, especially about 0.01 to 5 mg/kg of body weight per day, more particularly from 0.02 to 2.5 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used. A typical body weight is 70 kg.
The compounds in accordance with the invention may be prepared by a process which comprises cyclising a compound of formula III: 
wherein R1, L, W, X, Y and Z are as defined above.
The cyclisation of compound III may conveniently be effected by heating compound III to an elevated temperature, e.g. (i) a temperature in the region of 180-200xc2x0 C., in the presence of a high-boiling medium such as Dowtherm A; or (ii) at the reflux temperature of an inert solvent such as xylene, optionally in the presence of a proton source such as triethylamine hydrochloride.
The intermediates of formula III above may be prepared by reacting a compound of formula IV with a hydrazide derivative of formula V: 
wherein R1 , W, L, X, Y and Z are as defined above.
The reaction between compounds IV and V is conveniently effected by heating the reactants, optionally in the presence of a proton source such as triethylamine hydrochloride, typically at reflux in an inert solvent such as xylene.
In another procedure, the compounds of formula I as defined above wherein L represents O may be prepared by a process which comprises reacting a compound of formula VI with a compound of formula VII: 
wherein R1, W, X, Y and Z are as defined above, and G represents a suitable leaving group.
The leaving group G is suitably a halogen atom, typically chlorine.
The reaction between compounds VI and VII is conveniently effected by stirring the reactants in a suitable solvent, typically N,N-dimethylformamide, in the presence of a base such as cesium carbonate or potassium carbonate.
Similarly, the intermediates of formula IV wherein L represents O may be prepared by reacting a compound of formula VII as defined above with a compound of formula VIII or its keto tautomer: 
wherein R1 is as defined above; under conditions analogous to those described above for the reaction between compounds VI and VII; followed by oxidation.
Oxidation of the CH2OW side-chain in the intermediate resulting from the reaction between compounds VII and VIII to the aldehyde CHO side-chain in the corresponding intermediate of formula IV is suitably effected by treatment with manganese dioxide, in which case the reaction is conveniently carried out in chloroform at an elevated temperature in the region of 70xc2x0 C.
An alternative methodology can be used to make compounds where X is substituted by NR4R5C1-6alkyl. For example when the C1-6alkyl group is CH2 a compound of formula XVI:
HOxe2x80x94Yxe2x80x94Xxe2x80x94CH2xe2x80x94OPxe2x80x83xe2x80x83XVI
where X and Y are as defined above and P is a suitable protecting group such as TBS, is chlorinated, for example with thionylchloride generally in dichloromethane at about 0xc2x0 C. for about half an hour to give a compound of formula XVII:
Clxe2x80x94Yxe2x80x94Xxe2x80x94CH2OPxe2x80x83xe2x80x83XVII
where X, Y and P are as defined above. This compound is coupled to a compound of formula VI as described above to give a compound of formula XVIII: 
wherein L, R1, W, X, Y, Z and P are as defined above. The compound of formula XVIII can be deprotected to give a compound of formula I in which X is substituted by CH2OH. This compound can be mesylated, for example with MsCl generally in a solvent such as dichloromethane in the presence of a base such as triethylamine for about one hour at about room temperature. The resulting compound can be reacted with HNR4R5, where R4 and R5 are as defined above, to give the desired compound of formula I in which X is substituted by xe2x80x94CH2NR4R5.
When the C1-6alkyl is CH2CH2 a compound of formula XIX:
Clxe2x80x94Yxe2x80x94Xxe2x80x94CHCH2xe2x80x83xe2x80x83XIX
wherein X and Y are as defined above, is coupled to a compound of formula VI as described above to give a compound of formula XX: 
wherein L, R1, W, X, Y and Z are as defined above. Reacting with HNR4R5, where R4 and R5 are as described above, generally in a sealed tube in the presence of an acid such as acetic acid, and a solvent, such as methanol, produces the desired compound of formula I in which X is substituted by xe2x80x94CH2CH2NR4R5.
Compounds where the C1-6alkyl group in NR4R5C1-6alkyl is other than CH2 and CH2CH2 can be made by analogous methods.
In a further procedure, the compounds of formula I as defined above may be prepared by a process which comprises reacting a compound of formula IX with a compound of formula X: 
wherein R1, L, W, X, Y and Z are as defined above, and Gxe2x80x2 represents a suitable leaving group.
The leaving group Gxe2x80x2 is typically an arylsulfonyloxy moiety, e.g. p-toluenesulfonyloxy (tosyloxy).
The reaction between compounds IX and X is conveniently effected by stirring the reactants in a suitable solvent, typically N,N-dimethylformamide, in the presence of a base such as sodium hydride.
The intermediates of formula IX above may be prepared by reacting a compound of formula V as defined above with a compound of formula XI: 
wherein W, Z and Gxe2x80x2 are as defined above.
The reaction between compounds V and XI is conveniently effected by heating the reactants, optionally in the presence of a proton source such as triethylamine hydrochloride, typically at reflux in an inert solvent such as xylene.
In a still further procedure, the compounds of formula I as defined above may be prepared by a process which comprises reacting a compound of formula XII with a compound of formula XIII: 
wherein R1, L, W, X, Y and Z are as defined above, Gxe2x80x3 represents a suitable leaving group, and M represents xe2x80x94B(OH)2 or a cyclic ester thereof formed with an organic diol, e.g. 1,3-propanediol, or M represents xe2x80x94Sn(Alk)3 in which Alk represents a C1-6 alkyl group, typically n-butyl; in the presence of a transition metal catalyst.
The leaving group Gxe2x80x3 is typically a halogen atom, e.g. bromo.
Where M represents xe2x80x94B(OH)2 or a cyclic ester thereof, the transition metal catalyst is suitably tris(dibenzylideneacetone)palladium(O), in which case the reaction between compounds XII and XIII is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of tri-tert-butylphosphine and cesium carbonate.
Where M represents xe2x80x94Sn(Alk)3, the transition metal catalyst is suitably tetrakis(triphenylphosphine)palladium(O), in which case the reaction between compounds XII and XIII is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of copper(I) iodide.
The compounds of formula XIII above wherein L represents O may be prepared by reacting a compound of formula VII as defined above with a compound of formula XIV: 
wherein W, Z and Gxe2x80x3 are as defined above; under conditions analogous to those described above for the reaction between compounds VI and VII.
The intermediates of formula XIV in which the leaving group Gxe2x80x3 represents bromo may be prepared by bromination of a compound of formula XV: 
wherein W and Z are as defined above.
The bromination reaction is conveniently effected by treating the appropriate compound of formula XV with bromine, typically in glacial acetic acid.
The intermediates of formula VII and X above may be prepared by the procedures described in WO 98/04559, or by methods analogous thereto.
Where they are not commercially available, the starting materials of formula V, VI, VIII, XI, XII, XV, XVI, XIX and HNR4R5 may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. Indeed, as will be appreciated, the compounds of formula XIII in which Gxe2x80x3 is halogen are compounds according to the invention in their own right. By way of example, a compound of formula I initially obtained wherein X is unsubstituted may be converted into a corresponding compound wherein X is substituted, typically by standard alkylation procedures, for example by treatment with a haloalkyl derivative in the presence of sodium hydride and N,N-dimethylformamide, or with a hydroxyalkyl derivative in the presence of triphenylphosphine and diethyl azodicarboxylate. Furthermore, a compound of formula I initially obtained wherein the X substituent is substituted by a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the X substituent is substituted by a di(C1-6)alkylamino moiety by treatment with the appropriate di(C1-6)alkylamine, typically with heating in a solvent such as 1,4-dioxane in a sealed tube.
It will also be appreciated that where more than one isomer can be obtained from a reaction then the resulting mixture of isomers can be separated by conventional means.
Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The compounds in accordance with this invention potently inhibit the binding of [3H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the xcex15 subunit stably expressed in Ltk-cells.
Reagents
Phosphate buffered saline (PBS).
Assay buffer: 10 mM KH2PO4, 100 mM KCl, pH 7.4 at room temperature.
[3H]-Flumazenil (18 nM for xcex11xcex23xcex32 cells; 18 nM for xcex12xcex23xcex32 cells; 10 nM for xcex13xcex23xcex32 cells; 10 nM for xcex15xcex23xcex32 cells) in assay buffer.
Flunitrazepam 100 xcexcM in assay buffer.
Cells resuspended in assay buffer (1 tray to 10 ml).
Harvesting Cells
Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cmxc3x9725 cm) of cells.
Assay
Can be carried out in deep 96-well plates or in tubes. Each tube contains:
300 xcexcl of assay buffer.
50 xcexcl of [3H]-flumazenil (final concentration for xcex11xcex23xcex32: 1.8 nM; for xcex12xcex23xcex32: 1.8 nM; for xcex13xcex23xcex32: 1.0 nM; for xcex15xcex23xcex32: 1.0 nM).
50 xcexcl of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 xcexcM final concentration.
100 xcexcl of cells.
Assays are incubated for 1 hour at 40xc2x0 C., then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3xc3x973 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound.
The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [3H]Ro 15-1788 from the xcex15 subunit of the human GABAA receptor of 100 nM or less, most were at 50 nM or less, many were at 10 nM or less and some were at 1 nM or less.
The compounds of the present invention can be shown to enhance cognition in the rat water maze test (Morris, Learning and Motivation, 1981, 12, 239ff). This has been demonstrated for at least one compound described herein. Further details of methodology for demonstrating that the present compounds enhance cognition can be found in WO-A-9625948.